PROJECT SUMMARY: Current thinking has provided substantial support for the hypothesis that primary afferent and neuraxial neurogenic peptide receptors play a prominent role in pruritic pathologies. Of equal interest, is the growing appreciation that receptor signaling may also play a facilitatory role in inflammation in disease states. The confluence of these phenomena emphasize the likely importance of peripherally acting receptors in regulating aberrant sensations in pruritic states including atopic dermatitis (AD). Our data and literature support a link between neurogenic peptides to signaling by the Mas related GPCR family and that this signaling is governed by the transient receptor potential cation channel, member A1 (TRPA1). Accordingly, functional TRPA1 antagonists are expected to be key regulators of conditions like AD in terms of both pruritus and cutaneous inflammation. The goal of this application is to optimize one or more small molecule antagonists of the TRPA1 channel as a probe to study in vivo efficacy in animal models of AD. In this proposal, the drug discovery team at Epigen Biosciences Inc. will conduct a lead identification plan to identify novel small molecules with suitable drug like properties for pre-clinical evaluation of efficacy in preclinical models of atopic dermatitis. New compounds will be optimized for metabolic stability. Compounds with adequate in vitro profile will be studied at University of California San Diego (UCSD) in mice to identify compounds that prevent scratching responses. A lead compound will be further assessed in a preliminary model of atopic dermatitis for its ability to block behavioral responses and suppress preliminary markers of inflammation. Studies in atopic dermatitis will provide data on measures of dermal integrity [epidermal water loss and skin thickness], histopathology and measures of cytokine levels [protein and RNA from qPCR]. These data are expected to demonstrate the utility of novel TRPA1 antagonists in atopic dermatitis and support a lead optimization program as a prelude to commercial development. The lead compound will be then assessed for drug profile risk [cytochrome P450 and hERG inhibition] to guide future work.